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Title: Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1347756
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 59; Journal Issue: 18
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Wu, Yong-Jin, Guernon, Jason, Shi, Jianliang, Marcin, Lawrence, Higgins, Mendi, Rajamani, Ramkumar, Muckelbauer, Jodi, Lewis, Hal, Chang, ChiehYing, Camac, Dan, Toyn, Jeremy H., Ahlijanian, Michael K., Albright, Charles F., Macor, John E., and Thompson, Lorin A.. Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b01012.
Wu, Yong-Jin, Guernon, Jason, Shi, Jianliang, Marcin, Lawrence, Higgins, Mendi, Rajamani, Ramkumar, Muckelbauer, Jodi, Lewis, Hal, Chang, ChiehYing, Camac, Dan, Toyn, Jeremy H., Ahlijanian, Michael K., Albright, Charles F., Macor, John E., & Thompson, Lorin A.. Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors. United States. doi:10.1021/acs.jmedchem.6b01012.
Wu, Yong-Jin, Guernon, Jason, Shi, Jianliang, Marcin, Lawrence, Higgins, Mendi, Rajamani, Ramkumar, Muckelbauer, Jodi, Lewis, Hal, Chang, ChiehYing, Camac, Dan, Toyn, Jeremy H., Ahlijanian, Michael K., Albright, Charles F., Macor, John E., and Thompson, Lorin A.. 2016. "Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors". United States. doi:10.1021/acs.jmedchem.6b01012.
@article{osti_1347756,
title = {Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine β-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors},
author = {Wu, Yong-Jin and Guernon, Jason and Shi, Jianliang and Marcin, Lawrence and Higgins, Mendi and Rajamani, Ramkumar and Muckelbauer, Jodi and Lewis, Hal and Chang, ChiehYing and Camac, Dan and Toyn, Jeremy H. and Ahlijanian, Michael K. and Albright, Charles F. and Macor, John E. and Thompson, Lorin A.},
abstractNote = {},
doi = {10.1021/acs.jmedchem.6b01012},
journal = {Journal of Medicinal Chemistry},
number = 18,
volume = 59,
place = {United States},
year = 2016,
month = 9
}
  • A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit (3), with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores (10 and 23) were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180º in relation to the other. The amidine structural motif within each core forms a bidentate interaction withmore » a different aspartic acid of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates, as revealed by 3. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.« less
  • A number of novel amidine containing heterocycles were designed to reproduce the unique interaction pattern, revealed by X-ray crystallography, between the BACE-1 catalytic diad and a weak NMR screening hit, with special attention paid to maintaining the appropriate basicity and limiting the number of H-bonding donors of these scaffolds. The iminohydantoin cores were examined first and found to interact with the catalytic diad in one of two binding modes (A and B), each with the iminohydantoin core flipped 180° in relation to the other. The amidine structural motif within each core forms a bidentate interaction with a different aspartic acidmore » of the catalytic diad. Both modes reproduced a highly conserved interaction pattern between the inhibitors and the catalytic aspartates. Potent iminohydantoin BACE-1 inhibitors have been obtained, validating the molecular design as aspartyl protease catalytic site inhibitors. Brain penetrant small molecule BACE inhibitors with high ligand efficiencies have been discovered, enabling multiple strategies for further development of these inhibitors into highly potent, selective and in vivo efficacious BACE inhibitors.« less
  • Fragment-based NMR screening, X-ray crystallography, structure-based design, and focused chemical library design were used to identify novel inhibitors for BACE-1. A rapid optimization of an initial NMR hit was achieved by a combination of NMR and a functional assay, resulting in the identification of an isothiourea hit with a K{sub d} of 15 {micro}M for BACE-1. NMR data and the crystal structure revealed that this hit makes H-bond interactions with the two catalytic aspartates, occupies the nonprime side region of the active site of BACE-1, and extends toward the S3 subpocket (S3sp). A focused NMR-based search for heterocyclic isothiourea isosteresmore » resulted in several distinct classes of BACE-1 active site directed compounds with improved chemical stability and physicochemical properties. The strategy for optimization of the 2-aminopyridine lead series to potent inhibitors of BACE-1 was demonstrated. The structure-based design of a cyclic acylguanidine lead series and its optimization into nanomolar BACE-1 inhibitors are the subject of the companion paper (J. Med. Chem. 2010, 53, DOI:10.1021/jm901408p).« less